The candidate, Hossein Ardehali, M.D., Ph.D., is completing his training in Cardiovascular Medicine at the Johns Hopkins University Medical Center. As of July 1, 2004, he will be an Assistant Professor of Medicine in the Division of Cardiology at Johns Hopkins. The candidate has a solid interest in pursuing basic science research along with patient care in an academic institution. Johns Hopkins provides an excellent academic environment for young faculty to ensure their success in their scientific endeavors. Dr. Ardehali's mentor, Dr. Eduardo Marban, is a world-renown leader in cardiovascular biology, and his laboratory has an excellent track record of producing independent clinician scientists in cardiovascular biology. Dr. Ardehali's long-term goals are to become an independent investigator in the field of cardiobiology and to apply basic science discoveries to clinical practice with the hope of developing new treatments for ischemic heart disease. This proposal details Dr. Ardehali's research career development plan that integrates mentored research, didactic course work and professional scientific skills to launch a successful career as an independent investigator. Evidence suggests that brief ischemic episodes may invoke a process that can protect against future ischemic insults, a mechanism known as ischemic preconditioning (IPC). The mitochondrial ATP-sensitive K+ channel (mitoKATP) has been shown to be a key player in the process of IPC and is an inhibitor of apoptosis. However, the molecular structure of mitoKATP remains unknown. In preliminary data presented in this grant, the applicant has shown that a macromolecular protein complex in the mitochondrial inner membrane confers mitoKATP channel activity. The function of one member of this complex, mitochondrial ATP-Binding Cassett Protein-1 (mABC1) is not known, however, its yeast analog is thought to play a key role in protection against oxidant stress. The long-term objective of this proposal is to study whether mABC1 protein plays a role in protection of cells against ischemia and oxidant stress. In Aim 1, the applicant will evaluate the effect of mABC1 overexpression on cellular protection. In Aim 2, SiRNA technology will be used to downregulate mABC1 expression and study whether this would result in an exaggerated ischemic or oxidant damage to the cells. Aim 3 will focus on identifying substrate(s) that are transported by mABC1. The central thesis of this proposal is that mABC1 protein plays a key role in cellular protection against oxidant stress and ischemia. The experiments proposed herein are logical continuation of our attempt to understand the process of ischemic preconditioning and cellular protection against ischemia. The proposed development plan is designed to provide the mentorship, resources and supportive environment to build a successful career as an independent clinician scientist.